Thank you so much for that introduction, and hello everyone. So my presentation today is going to be called Choosing the Right Drug, and what we're going to talk about today is we're going to describe pharmacotherapy for pulmonary arterial hypertension in the critically ill patient population. Now this is a topic that, honestly, we can talk many, many hours about. However, what I wanted to focus on today is to really answer the question of, we have this PAH patient that's on all of these medications, and now they're admitted to my ICU. What do I do with these medications? So just to make sure that we're all on the same page, we're going to briefly talk about the background of some of these medications. So this is a timeline of the treatment options that are available. You know, we've come a long way in the last several years. We first started out in 1995 with IV proprosinol, which is the only medication that we had in our armamentarium for several years, until maybe six years later, we had other options present, like Bosentan. Since then, we have expanded our options to include different routes, PO, inhaled, subcutaneous, as well as different medication classes. And most recently, not pictured here, is the new agent, Cetatorcept, that is gonna come on the market shortly. So the different drug classes that we have can be categorized into one of three different pathways. We have the prostacycin pathway, the endothelin pathway, and the nitric oxide pathway. So the prostacycin pathway was the first one that we had medications for. So what we have here is, in a normal, healthy patient, in the vascular endothelial cells, the arachidonic acid's gonna be converted into prostacycline, which is then released. The prostacycline's gonna sit on the IP receptor of the smooth muscle cell, and that's gonna result in vasodilation and antiproliferation. However, in pH patients, their endogenous prostacycline levels are low, so that's gonna lead to very severe vasoconstriction and remodeling of their pulmonary arteries. So since, in this patient population, the prostacycline levels tend to be low, one of the solutions that we came up with is to reintroduce prostacycline into these patients. So we have our prostacycline analogs, iproprosinol being the first one on the market, very structurally similar to our own endogenous prostacycline. And then we had traprosinol and ilopros that also entered the market. And then in 2015, we came out with celexipag, which is a prostacycline receptor agonist. Next on the market, we had drugs with the endothelin pathway. So endothelin-1 is one of the most potent vasoconstrictors in the body. So endothelin-1, when it's released by the vascular endothelial cells, it's gonna bind to one of two receptors, and these two receptors have very different properties. So if it binds to the ETA receptor, what tends to happen is it's going to promote very intense vasoconstriction. However, if it binds to the ETB receptor, it will actually vasodilate because it's gonna cause an increase in our endogenous prostacycline release and nitric oxide release, and it's actually gonna facilitate clearance of our endothelin-1. So theoretically, if we were to make a drug in this pathway, we're gonna want a drug that preferentially binds to the ETA receptor and tries to leave the ETB receptor alone. So when the drugs came out on the market, we have bosentan, which was the first one. That one is a dual ETA and an ETB receptor antagonist, but it does have slightly better potency for the ETA receptor over the ETB. Next, we had embrosentan that came out. That one is exclusively an ETA receptor antagonist. And then we had masatentan, which is also a dual antagonist. However, it's 50 times more specific for the ETA receptor over the ETB. Now, it's important to note that although theoretically, preferential binding of the ETA receptor is something that we look forward to, however, in clinical trials, these weren't compared to head-to-head, so the clinical benefit of select ETA receptor availability or selectivity is unknown so far. And lastly, we have our nitric oxide pathway, and here we have our phosphodiesterase inhibitors and our soluble guanylate cyclase stimulator. So in PH patients, the endogenous nitric oxide levels are going to be low. One solution to that is we can give them inhaled nitric oxide, however, that's not a therapy that we can really send our patients home on and maintain them on. So one of the things that we have done is we have created phosphodiesterase inhibitors. So in the body, nitric oxide is going to stimulate the soluble guanylate cyclase to move the reaction forward and increase the cyclic GMP levels in our cells. Now, with an increase of cyclic GMP levels, it's going to create vasodilation and antiproliferation, but in the body, the phosphodiesterase enzyme will actually break down the cyclic GMP. So one of our solutions is by using a phosphodiesterase inhibitor to prevent the breakdown of cyclic GMP in the body. Specifically, phosphodiesterase 5 is the enzyme that is most prevalent in the lungs. So for our phosphodiesterase 5 inhibitors, we have sildenafil and tadalafil that are FDA approved for this indication. Of note, vardenafil is the other PDE5 inhibitor. It has been studied in pulmonary arterial hypertension, however, it's not as selective for PDE5 as these other two agents are. So it tends to cause more hypertension in these patients, which is why it's not FDA approved. And lastly, we have, apologies, Rio-Ciguat, which is the soluble guanylate cyclase stimulator. So this drug is interesting because it has a dual mechanism of action. It's going to independently stimulate the soluble guanylate cyclase, independent of endogenous nitric oxide, apologies. And it's also going to sensitize the soluble guanylate cyclase to our endogenous nitric oxide. Apologies about that. So, now that we know about these medications, what do we do with these patients when they're admitted? Sorry about that, everyone, my throat is very dry. So I'm going to take you through some cases here. So we have patient one. This is a 75-year-old male who's on their immunity pump at home. He's admitted to the medical ICU with hypoxemic respiratory failure. So sorry, secondary COVID pneumonia, and then he's subsequently intubated. So this patient, they weigh him in the medical ICU, and they see that his weight is 98.5 kilos. And according to previous admission records, his immunity pump was set at 19 nanograms per kilo per minute. So sorry. So what issue are we facing here? Well, for parenteral process icons, we have two agents that are on the market. We have epiprocinol, which is the original drug, that is still sometimes referenced as Flolan or Velitri. Epiprocinol has a half-life of only about five minutes, so it can only be given intravenously via an infusion pump. Now, when this first came out on the market, it was very cumbersome for our patients to use. Because of the very short half-life, this pump, this medication needed to have a backup medication pump and a medication cassette available at all times. So when triprocinol came out on the market, it was the patient favorite. So it had a half-life of four hours, and because of that, we were able to expand it to oral subcutaneous and inhaled routes. So specifically to our patient, they're on the subcutaneous route. So the subcutaneous route currently has two pumps available. The original CAD MS-3 pump, which personally I found to be a very cumbersome pump to use, this pump has now been discontinued by Smith Medical. However, we might still see patients on this pump until they can get transitioned to the new Rimmunity pump. The Rimmunity pump, the Rimmunity pump that we see here is a very intuitive pump. I'm so sorry. It has the round medication cassette that you see here, and it also has a handheld programmable device that the patient can use. So they can actually modify their rate and program it discreetly. However, the issue with these pumps is, at most institutions, most of the RNs are not actually trained on how to utilize these pumps. So if you have a patient that comes into your institution, oftentimes we'll have these patients continue on their own medication pumps, assuming that they are able to actively manage it while they're inpatient. However, if the pump malfunctions, or if, in our patient's case, they're intubated, or they're sedated and they can't interact with their pump, we have to convert the patient to a hospital-supplied pump, which is going to be intravenous. But how do we convert our patient intravenously? Well, data from this particular study showed that the concentrations of the prostacyclotriprosyl when it's given subcutaneously versus when it's given intravenously are actually pretty linear when it's between the rates of 15 to 125 nanograms per kilo per minute. So in the case of our patient, we can actually do a one-to-one conversion to an IV doprosinone. Now, this medication is preferred to be given centrally, but it can be given peripherally for a period of time. However, at our institution, since peripheral lines, as we know, can be lost quite frequently, we recommend that if we're giving it peripherally, that we have at least two dedicated peripheral lines in case one of those lines goes down. The switch can be made instantaneously. There's no need to overlap therapy, so you can stop one and start the other. And one thing that I want to stress is these parenteral prostacyclines are available via limited distribution from a specialty pharmacy, such as a Credo or CVS Caremark. It is imperative that when we have these patients come into our ICU, we call their specialty pharmacy because we need to figure out what their dosing weight is. Now, their dosing weight is the weight that the patient is... I'm so sorry. Their dosing weight is the weight that they are when the pump is first started. This weight does not change for the patient regardless of any weight fluctuations that the patient's going on. So as I mentioned in my example here, we weighed the patient in the medical ICU. Their weight was 98.5 kilos. However, when we called the Credo, we found that their weight was actually 80 kilos based on their dosing weight. So by calling their specialty pharmacy, we prevented accidentally overdosing the patient's medication. Now, IV triprosanol, when it's given intravenously, the cassette is stable for 48 hours. So what we'll do is we'll use their dose, their dosing weight to figure out what concentration we'll need for the infusion. So ideally, we want to figure out how much they're gonna need in a 48-hour period. So in this patient, they'll need about 4.3 million nanograms. Now at Yale, we have these concentrations pre-built in Epic in increments of 500,000 to a million nanograms, and that's to prevent user error in entering the different concentrations. So for this patient, I might pick a concentration of 4.5 million nanograms in 100 mL or five million nanograms in 100 mL. It's important to note that whether your patient is on subcutaneous prostacyclines or they're on intravenous prostacyclines, most of these medications are not going to be compatible with MRI because the pumps are not compatible. So if your patient is on a subcutaneous pump and they need to get this procedure done, then we advise that the providers notify pharmacy at least like an hour or two ahead of time so that we can create an IV cassette for these patients. So you'll convert them to IV for the duration of their procedure, and once they come back for the MRI, you can switch them back onto their subcutaneous pump. I don't think that's advancing anymore. Oh, there we go, okay. So for patient two, this is a patient who was brought in after a mechanical fall, brought into the neuro-ICU, and had a subdural hematoma. This patient gets intubated for airway protection, and they're on the Tyvaso inhalation system at 54 micrograms four times daily. So the question is, can we administer Tyvaso through the patient's mechanical ventilator? And there were a few studies that looked at that. So of note, all of these studies, they're pharmacokinetic studies. There are no patients involved. So in the first study from 2007, what they did is they actually nebulized Iloprost through a breath-actuated ventilator circuit. Now what this does is it will only nebulize the medications when it senses that the patient is doing an inhalation. So using this breath-actuated ventilator circuit, they found that, yes, the patients were able to get a clinically meaningful dose of Iloprost. However, most institutions probably do not utilize a breath-actuated ventilator circuit. So what do you do for those patients that, well, we don't have that device? That's what the next two studies sought to answer. So in those studies, what we'll see is they were trying to target a dose of 54 micrograms for the patient. However, an issue with nebulizing these medications continuously is a large chunk of that medication is going to be lost when it's nebulized during the patient's expiratory phase. So what these studies sought to do is they adjusted the dose to account for the amount of drug that gets lost when the patient's doing exhalation. But the dosing that they had to give depended very widely on what the ventilator settings were and what kind of nebulizer device they used. So for example, to reach a target dose of 54 micrograms, the 2013 study needed to nebulize about 72.2 micrograms, whereas the last 2017 study, they needed to nebulize about 216 micrograms to get that target dose. So as you can see, the dosing range is very wide and that's not yet practical to do. So unless your institution has a breath-actuated ventilator circuit, at this time there's really insufficient data to say that you can nebulize these medications through the mechanical ventilator circuit and have the patient still get the same dose. So what can you do and what do we do instead? Well, a key drug in our armamentarium is going to be our inhaled pulmonary vasodilators. And there's currently two that are available that we use. So we have inhaled nitric oxide and we have inhaled epiprocinol. Now which drug your institution uses can be based on a wide variety of factors. In terms of efficacy, there's no difference in terms of mechanical vent-free days or oxygenation for the patients according to the studies. However, where we do see a difference between these agents is going to be in the safety monitoring that is required and in the cost. So for example, inhaled nitric oxide tends to be a little bit more expensive for the institutions because it does require a specific setup. But in terms of safety, inhaled nitric oxide, if you're giving prolonged doses of inhaled nitric oxide and doses greater than 80 parts per million, you can put your patient at risk of developing methemoglobinemia. So if your patient is on this therapy continuously, we do recommend daily methemoglobin levels. For inhaled epiprocinol, this medication is one that's usually going to be compounded in your IV room. And as a result, it's going to look identical to every other IV medication that you have. So one thing that we make sure that we do is we safeguard this medication from accidentally being given intravenously because if it is given intravenously, it can cause precipitous hypotension in patients if used improperly. The nice part about these medications is that they're very flexible and they're a great tool for us to have in other situations with our patients. So for example, if we have a hemodynamically unstable PH patient present to the ICU and we want to start them on an IV prostacyclin or we want to up titrate their prostacyclin but they're hemodynamically unstable and we don't want to start that therapy yet, we can start them on inhaled pulmonary vasodilator as a temporizing measure. But what about our oral PH medications? If our patient is intubated and has a gastric tube, do we need to utilize an inhaled pulmonary vasodilator for these medications if they're unable to take them? Well, the answer is it depends. So here we have the different oral medications separated into their respective pathways and as we can see here, majority of these medications come with a package warning to not crush the medications. However, there are a wide variety of things that we can do for these oral medications and that's what we'll be focusing on from here on out. One of the nice things is that some of these medications like Bosentan, it is available as a dispersible tablet so that one can actually be dissolved in water and given to the patient and then Sildenafil and Tadalafil do have extemporaneous compounding recipes. But what about our ERAs and Rio Ciguat? Different medications can have a do not crush label for a wide variety of reasons and for the ERAs and Rio Ciguat, the reason behind this is because of their teratogenicity. So NIOSH categorizes these as group three, non-antineoplastic drugs that have primarily reproductive effects. If you have a nurse that is handling these medications and providing them to the patient, they can go ahead and do that with a single layer of gloves as long as they're utilizing intact tablets. However, if we need to crush these medications, then NIOSH recommends that this is done under a biosafety cabinet, so a chemotherapy hood and that the person who is mixing these medications is donning the proper PPE. There's also no compounding data for any of these agents. So what our institution will do is we will actually crush these medications under a biosafety cabinet, so a chemotherapy hood. We will mix in about 10 to 15 mLs of sterile water and because there's no stability data for these agents, the compound only has a stability shelf life of one hour. So what this means is this will have to be mixed and immediately administered. So this can pose logistical challenges for some institutions. Some institutions may not have a chemotherapy hood. Due to staff shortages, you may not have a technician available to be able to run up the medication immediately after it's mixed and you'll have to educate your nurses that once they receive this medication, they need to immediately give it because it has a very short stability. If all of those items do not apply to your institution, then in the worst case scenario, these drugs can be held temporarily until the patient is able to resume taking oral medications. What about drugs like traprosanil? That one poses a different challenge because with traprosanil, that medication, if it's abruptly discontinued, it can cause rebound pulmonary hypertension and your patient can decompensate. So in this patient scenario, we have a 75 kilo patient brought into the near ICU with new onset seizures and is again intubated for airway protection. We find that this patient is on Oranatram, 3.25 milligrams every eight hours. So what can we do? Well, one thing that is a potential option actually comes straight from the package insert of the drug. Here we see the formula where you can convert the IV remodulin dose if a patient is on into Oranatram equivalents. Now in this situation, the X that we are solving for is the equivalent remodulin dose for this patient. So in this scenario, based on his oral Oranatram dose, the equivalent IV dose would be approximately 18 nanograms per kilo per minute. A potential benefit of doing this strategy is that it would be a very quick transition and depending on the inhaled agent of choice at your institution, you could potentially prevent your patient from developing methemoglobinemia if you're using inhaled nitric oxide. A con is that this could be a potentially bold strategy to use and the reason why I say bold is when you look at the data behind this particular formula, it actually comes from outpatient studies where they are trying to take patients who are on IV remodulin and titrate them over onto oral Oranatram. And the way that they do this transition in the outpatient setting is they'll cross titrate. They'll titrate down their remodulin slowly while they up titrate the oral traprosanil and this is a process that's done over several days to weeks. So doing it as a stop one and start the other can be potentially bold. A modified version of this strategy that you could employ is you could potentially start your patient on a lower dose of IV remodulin and then just rapidly titrate up to a rate of 18 nanograms per kilo per minute. So this is something that our institution will sometimes do. We'll start patients at a dose of about two to four and rapidly titrate up to, in this case, 18 nanograms per kilo per minute. And then we can utilize our inhaled pulmonary vasodilators as an alternative option. Especially if we're at an institution where we may not have IV traprosanil available. So in that situation, utilizing the inhaled pulmonary vasodilators is definitely an option that we can employ. Selexipag is an interesting medication. So what if our patient in the previous example was on Selexipag instead? Well, I'm going to walk you through three potential strategies that you can do. The first strategy comes from the 2015 Griffin study. So in this study, what they did is they titrated up Selexipag to the highest tolerated dose and then that patient entered the maintenance phase. Patients were allowed to have treatment interruptions in this study and they monitored these patients when treatment was interrupted. So what they found was, unlike agents like traprosanil, for example, where if you abruptly discontinue it, these patients can decompensate. With Selexipag, these patients actually tolerated the treatment discontinuations very well. However, if the dose was discontinued for more than three days, at that point, it is recommended that you restart the patient at a lower dose and titrate up. So that is one potential option that you can do for your patients since Selexipag is enteric code and is recommended not to be crushed. However, for me personally, I know at many institutions, sometimes when medications, when home medications are held, it can sometimes fall through the cracks when the patient is getting discharged and the patient can sometimes not be restarted on their home medications. So there are other options that we can use if that's not a method that we are comfortable with. The other alternative is recently, there's an IV Selexipag option that entered the market. What's interesting about IV Selexipag is with most IV medications, when you're doing an IV to PO conversion, the ratios are usually one to one or the IV dose is actually a little bit lower than the oral dose because of increased bioavailability. With Selexipag, it's interesting because Selexipag, the parent drug, is actually less pharmacologically active than its active metabolite. So pharmacokinetic study looked at the concentration of the active metabolite when it's given PO versus inhaled and they found that with the oral administration, there's a higher concentration of the active metabolite. So to compensate for that, it's recommended that you increase the IV Selexipag dose by 12.5% to make sure that they're getting the same concentration. The IV Selexipag also has special administration requirements. It's an 80-minute infusion. It has to be given through a DHP-free infusion set and protected from light. And then when you're administering the medication, it's recommended to spike a bag of normal saline afterwards to flush the line to make sure that your patient's getting the entire dose. Depending on the infusion sets that your institution is using, that can be about like 20 to 30 mLs that's lost in the line if you don't flush the line afterwards. Now, this third option is one that some institutions have been using and this is a very off-label use of the drug. So if you look at the package insert of Selexipag, it states do not crush, split, or chew the tabs. However, it doesn't go into much detail about why. When you look at Janssen's medical information, it's because Selexipag, the medication itself, is actually very sensitive to light and it has that film coating there to protect it from the light. Now, when you continue to look through different data, there's the European Medicines Agency that has a report that states that when it's exposed to light for a significant number of hours, it develops three different impurities in the product. So upon further digging, we found that the European Medicine Agencies utilize the QMB photostability testing guidelines, which state that they expose a sample to light for a significant number of hours. However, they do not specify what that hour timeframe is. So what some institutions have done is they have actually crushed Selexipag and immediately administered the medication. So just crush in an area that's not directly exposed to light and then just immediately administer it to the patient. One potential caveat of this is that since it is a film coating, that film coating can be quite tough to crush and you have to make sure that you crush the film coating well just to make sure that it doesn't clog the patient's gastric tube. But that is a third option for Selexipag that we can do. So in summary, our critically ill patients with PH, they do pose a number of logistical challenges with their medications. And it's important to note that if they have medications that are going to be self-administered, that we take a look at whether or not these patients are capable of managing their medications while they're inpatient. And if not, the good news is we do have a number of different strategies that we can employ to take care of these patients. And we do have our inhaled pulmonary vasodilators, which can be good workhorses for all of our patients. Thank you so much everyone for your time and I hope I served as a good resource for you.

pharmacotherapy

pulmonary arterial hypertension

critically ill patients

ICU

prostacyclin pathway drugs

endothelin pathway drugs